In a special breeding project with the goal of developing one or more models of autoimmune disease, we bred rabbits within our colony for susceptibility to disease induction. The initial focus of our study was a rabbit model of human Systemic Lupus Erythematosus (SLE). It is known that in man some genes affect susceptibility to several different autoimmune diseases. Thus selective breeding may result in broader susceptibility to autoimmune diseases. SLE is a complex, chronic autoimmune disorder that predominately affects young women. Clinical symptoms may include rash, arthritis, nephritis, and neurological disruption (including cognitive decline, seizures, psychosis). SLE is characterized by the production of autoantibodies to various nuclear antigens and double-stranded DNA (dsDNA). We immunized groups of rabbits with an NMDA glutamate receptor-derived peptide on a multiple antigen peptide backbone (BB) based on reports that some anti-DNA antibodies from mice and from lupus patients cross react with the NR2 glutamate receptor, and extending earlier published reports, we also immunized rabbits with an Sm B/B-prime-derived peptide on BB. Immunization with these two different peptide immunogens led to development of anti-dsDNA antibodies, and other correlates of human SLE. Comparisons of preimmune and post-immunization sera suggest that levels of anti-dsDNA and antinuclear antibodies have increased in some MAP-peptide immunized rabbits. Rabbits from both immunization groups with high anti-dsDNA responses were observed to experience seizures. Our studies confirm one earlier report that used Sm peptide immunization to induce SLE-like serology in non-pedigreed rabbits, and extend the studies to a new peptide immunogen (Rai et al J.Immunol 176:660-7, 2006,). The use of our unique pedigreed rabbits will expedite understanding the interactions of genetic susceptibility with exposure to defined external immunogens leading to SLE-like manifestations. Studies of a fifth group of 24 relatives and progeny from the first four groups of immunized rabbits have been completed and studies of groups of six animals each (6A,B ,C and D) are currently in progress. We cloned and sequenced the rabbit homologs of Blys (BAFF) and its receptor BR3 and have been analyzing sera and tissues of affected rabbits. Results of mRNA expression analyses on DNA microarrays and protein microarray analyses of autoantibodies in sera are currently being analyzed.